Use of novel cytokine receptors as biomarkers and therapeutic targets in human cancer

ABSTRACT

Nucleic acids encoding erythropoietin isoforms are described herein, as well as the encoded isoforms, methods of detecting the same, and methods of screening for and treating cancer.

FIELD OF THE INVENTION

[0001] The present invention concerns nucleic acids encodingerythropoietin receptor isoforms, proteins encoded by such nucleicacids, antibodies that bind to such proteins, and methods of using thesame.

BACKGROUND OF THE INVENTION

[0002] Erythropoietin (Epo) is the principal hematopoietic growth factorthat promotes the viability, differentiation and proliferation ofmammalian erythroid progenitor cells (S. Krantz, Blood 77, 419-34(1991)). The biologic effects of Epo are mediated via its interactionwith its specific transmembrane receptor, EpoR (H. Youssoufian, Blood81, 2223-36 (1993)). The EpoR lacks intrinsic tyrosine kinase activityand upon ligand binding activates a receptor-associated tyrosine kinaseJak2 which is critical for anti-apoptosis and mitogenic signaling viathe EpoR (O. Miura et al., Blood 84, 1501-7 (1994); B. Witthuhn et al.,Cell 74, 227-36 (1993); J. Ihle, Nature 337, 591-4 (1995); H. Zhuang etal., J Biol. Chem. 270, 14500-4 (1995)). Activated Jak2 thenphosphorylates a number of cytoplasmic proteins as well as the EpoRitself. Expression of Epo receptors has been reported on severalnon-hematopoietic cell types including vascular endothelial cells,placental tissue, neuronal cells, kidney and cardiomyocytes (A.Anagnostou et al., Proc. Natl. Acad. Sci. USA 91, 3974-8 (1994); S.Masuda et al., J. Biol. Chem. 268, 112-8-16 (1993); S. Sawyer et al.,Blood74, 103-9 (1989); M. Wald et al., J. Ce. Physiol. 167, 461-8(1996)).

[0003] Recombinant human Epo (r-HuEpo) has been widely used in manydifferent types of cancers for the treatment or prevention ofchemo-radiotherapy induced anemia (A. Moliterno and J. Spivak, Hematol.Oncol. Clin. North Am. 10, 345-63 (1996)). For instance, in patientswith breast cancer, r-HuEpo has been investigated in clinical trials forits potential beneficial effects in the prevention or treatment ofchemotherapy or radiation therapy-related anemia (L. Del Mastro et al.,J. Clin. Oncol. 15, 2715-21 (1997); H. Ludwig et al., Ann. Oncol. 4,161-7 (1993); P. Sweeney et al., Br. J. Cancer 77, 1996-2002 (1998); S.Vijayakumar et al., Int. J. Radiat. Oncol. Biol. Phys 26, 721-9 (1993)),for mobilization of peripheral blood progenitor cells (C. Waller et al.,Bone Marrow Transplant 24, 19-24 (1999)), to increase the rate ofhematopoietic recovery following high dose chemotherapy (P. BenedettiPanici et al., Br. J. Cancer 75, 1205-12 (1997); S. Filip et al.,Neoplasma 46, 166-72 (1999)) as well as use in ex vivo expansionstrategies of stem cells (C. Bachier et al., Exp Hematol. 27, 615-23(1999); L. Pierelli et al., Exp. Hematol. 27, 416-24 (1999); P. Stiff etal., Blood 95, 2169-74 (2000); W. Vogel et al., Blood 86, 1362-7(1996)). Similarly, r-HuEpo has been investigated in several clinicaltrials of squamous cell cancers of head-neck (F. Dunphy et al., Cancer86, 1362-7 (1999); M. Henke et al., radiother Oncol 50, 185-90 (1999);G. Mantovani et al., Oncol. Rep. 6, 421-6 (1999)) and uterine cervix (K.Dusenbery et al., Int. J. Radiat. Oncol. Biol. Phys. 29, 1079-84(1994)).

[0004] In view of the foregoing, it would be extremely desirable tounderstand the association of Epo with tumor growth and how EpoR may beinvolved in cancer pathophysiology and progression.

SUMMARY OF THE INVENTION

[0005] A first aspect of the present invention is an isolated nucleicacid encoding erythropoietin isoform 1, erythropoietin isoform 2,erythropoietin isoform 3, erythropoietin isoform 4, or erythropoietinisoform 5, or a nucleic acid that encodes the opposite or complementarystrand of a nucleic acid as set forth above (e.g., a DNA encoding anRNA).

[0006] A second aspect of the present invention is a protein encoded bya nucleic acid as described above (e.g., an isolated and/or purifiedprotein).

[0007] A third aspect of the present invention is an antibody thatselectively or specifically binds to a protein as described above.

[0008] A further aspect of the present invention is an oligonucleotideprobe that selectively or specifically binds to a nucleic acid asdescribed above.

[0009] A further aspect of the present invention is a method ofscreening a subject for cancer, comprising: detecting the presence orabsence of a nucleic acid encoding an isoform as described above in thesubject, the presence of such a nucleic acid indicating the subject isafflicted with or at risk of developing cancer.

[0010] A further aspect of the present invention is a method ofscreening a subject for cancer, comprising detecting the presence orabsence of a protein or isoform as described above in the subject, thepresence of such a protein indicating the subject is afflicted with orat risk of developing cancer.

[0011] Particular cancers which may be screened by the methods describedherein include, but are not limited to, breast, cervix, ovarian,prostate, colon and lung cancer.

[0012] The foregoing and other objects and aspects of the presentinvention are explained in detail in the drawings herein and thespecification set forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1. The organization of the EpoR gene (GenBank accessionnumber S45332, SEQ ID NO: 1). The splicing that results in the maturemRNA for the wild-type receptor (SEQ ID NO: 3), and five alternativelyspliced isoforms (1-5) described herein are depicted schematically. Thetranslated regions of the gene are indicated in black, whereasuntranslated regions are indicated in white. Novel amino acidtranslations that result from alternative splicing of the EpoR genetranscript are indicated in grey.

[0014]FIG. 2. Changes in the open reading frames (ORFs) of mature mRNAsequences from the full-length wild-type receptor in the isoforms ofEpoR described herein. Isoform 1 (SEQ ID NO: 4): Additional nucleotidesfrom intron 6 (nucleotides 5949-6062, SEQ ID NO: 1) are spliced betweenexons 6 and 7. Isoform 2 (SEQ ID NO: 6): Splicing at the 5′ end of exon8 occurs 19 nucleotides upstream (nucleotide 7498) from that seen in thefull-length wild-type message (nucleotide 7517). Isoform 3 (SEQ ID NO:8): Intron 7 is not spliced out of the final message. Isoform 4 (SEQ IDNO: 10): Intron 5 is not spliced out of the final message. Isoform 5(SEQ ID NO: 12): exon 6 is skipped, with exon 5 spliced directly to exon7. Putative C-terminal amino acid sequence changes from wild-type EpoRare depicted in bold.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. In addition,numerous variations and additions to the various embodiments suggestedherein will be apparent to those skilled in the art in light of theinstant disclosure which do not depart from the instant invention.Hence, the following specification is intended to illustrate someparticular embodiments of the invention, and not to exhaustively specifyall permutations, combinations and variations thereof.

[0016] Nucleic acid as used herein refers to any type of nucleic acid,including naturally occurring and synthetic nucleic acids and includingboth DNA and RNA.

[0017] Subjects with which the present invention may be carried out aregenerally mammalian subjects, including both human subjects andnon-human subjects (e.g., dog, cat, horse, rabbit, rat) for veterinaryor research purposes.

[0018] Any type of antibody may be used in the present invention. Theterm “antibodies” as used herein refers to all types of immunoglobulins,including IgG, IgM, IgA, IgD, and IgE. Of these, IgM and IgG areparticularly preferred. The antibodies may be monoclonal or polyclonal(with monoclonal antibodies preferred) and may be of any species oforigin, including (for example) mouse, rat, rabbit, horse, or human.See, e.g., M. Walker et al., Molec. Immunol. 26, 403-11 (1989). Antibodyfragments that retain specific binding to the protein or epitope boundby the antibody are included within the scope of the term “antibody” andinclude, for example, Fab, F(ab′)2, and Fc fragments, and thecorresponding fragments obtained from antibodies other than IgG. Suchfragments can be produced by known techniques. The antibodies may bechimeric or humanized, particularly when they are used for therapeuticpurposes.

[0019] Applicants specifically intend that all United States patentreferences cited herein be incorporated herein by reference in theirentirety.

[0020] 1. Nucleic acids.

[0021] As noted above, a first aspect of the present invention is anucleic acid encoding an erythropoieitin receptor isoform as describedherein. In certain embodiments the nucleic acid may be an RNA such as anmRNA, or may be a DNA.

[0022] In one embodiment, the nucleic acid encodes erythropoietinreceptor isoform 1 and has the sequence given herein as SEQ ID NO: 4.

[0023] In another embodiment, the nucleic acid encodes erythropoietinreceptor isoform 2 and has the sequence given herein as SEQ ID NO: 6.

[0024] In another embodiment, the nucleic acid encodes erythropoietinreceptor isoform 3 and has the sequence given herein as SEQ ID NO: 8.

[0025] In another embodiment, the nucleic acid encodes erythropoietinreceptor isoform 4 and has the sequence given herein as SEQ ID NO: 10.

[0026] In another embodiment, the nucleic acid encodes erythropoietinreceptor isoform 5 and has the sequence given herein as SEQ ID NO: 12.

[0027] In another embodiment, the nucleic acid that encodes the oppositestrand of a nucleic acid as set forth above (e.g., is a DNA encoding anRNA).

[0028] Nucleic acids as described above may be natural or synthetic, andcan be produced in accordance with techniques known in the art orvariations thereof which will be apparent in light of the disclosureherein.

[0029] Nucleic acids as described above may be coupled to appropriateregulatory elements such as a promoter to produce a recombinant nucleicacid construct, which construct may be inserted into a host cell inwhich the promoter is operable so that the encoded protein is expressedby the host cell. Recombinant techniques and the production of proteinsin recombinant cells may be carried out in accordance with knowntechniques.

[0030] 2. Antibodies.

[0031] Polyclonal antibodies used to carry out the present invention maybe produced by immunizing a suitable animal (e.g., rabbit, goat, etc.)with the antigen to which the monoclonal antibody binds, collectingimmune serum from the animal, and separating the polyclonal antibodiesfrom the immune serum, in accordance with known procedures. Depending onthe host species, various adjuvants may be used to increaseimmunological response. Such adjuvants include, but are not limited to,Freund's, mineral gels such as aluminum hydroxide, and surface activesubstances such as lysolecithin, pluronic polyols, polyanions, peptides,oil emulsions, keyhole limpet hemocyanin, and dinitrophenol. Amongadjuvants used in humans, BCG (bacilli Calmette-Guerin) andCorynebacterium parvum are especially preferable.

[0032] Monoclonal antibodies of the present invention may be preparedusing any technique which provides for the production of antibodymolecules by continuous cell lines in culture. These include, but arenot limited to, the hybridoma technique, the human B-cell hybridomatechnique, and the EBV-hybridoma technique (Kohler, G. et al. (1975)Nature 256:495-497; Kozbor, D. et al. (1985) J. Immunol. Methods81:31-42; Cote, R. J. et al. (1983) Proc. Natl. Acad. Sci. 80:2026-2030;Cole, S. P. et al. (1984) Mol. Cell Biol. 62:109-120). Briefly, theprocedure is as follows: an animal is immunized with antigen orimmunogenic fragments or conjugates thereof. For example, haptenicoligopeptides of antigen can be conjugated to a carrier protein to beused as an immunogen. Lymphoid cells (e.g. splenic lymphocytes) are thenobtained from the immunized animal and fused with immortalizing cells(e.g. myeloma or heteromyeloma) to produce hybrid cells. The hybridcells are screened to identify those which produce the desired antibody.

[0033] Human hybridomas which secrete human antibody can be produced bythe Kohler and Milstein technique. Although human antibodies areespecially preferred for treatment of human, in general, the generationof stable human-human hybridomas for long-term production of humanmonoclonal antibody can be difficult. Hybridoma production in rodents,especially mouse, is a very well established procedure and thus, stablemurine hybridomas provide an unlimited source of antibody of selectcharacteristics. As an alternative to human antibodies, the mouseantibodies can be converted to chimeric murine/human antibodies bygenetic engineering techniques. See V. T. Oi et al., Bio Techniques4(4):214-221 (1986); L. K. Sun et al., Hybridoma 5 (1986).

[0034] In addition, techniques developed for the production of “chimericantibodies”, the splicing of mouse antibody genes to human antibodygenes to obtain a molecule with appropriate antigen specificity andbiological activity can be used (S. L. Morrison, et al. Proc. Natl.Acad. Sci. 81, 6851-6855 (1984); M. S. Neuberger et al., Nature312:604-608 (1984); S. Takeda, S. et al., Nature 314:452-454 (1985)).Alternatively, techniques described for the production of single chainantibodies may be adapted, using methods known in the art, to produceisoform-specific single chain antibodies. Antibodies with relatedspecificity, but of distinct idiotypic composition, may be generated bychain shuffling from random combinatorial immunoglobin libraries (D. R.Burton, Proc. Natl. Acad. Sci. 88, 11120-3 (1991)).

[0035] Antibodies may also be produced by inducing in vivo production inthe lymphocyte population or by screening immunoglobulin libraries orpanels of highly specific binding reagents as disclosed in theliterature (R Orlandi et al., Proc. Natl. Acad. Sci. 86, 3833-3837(1989)); G. Winter et al., Nature 349, 293-299 (1991)).

[0036] Antibodies that selectively bind to a particular erythropoietinreceptor isoform as described herein (i.e., that selectively bind to oneof isoforms 1-5 but do not bind to the other of isoforms 1-5) can beidentified in accordance with known techniques, such as their ability tocompete with labeled antibody to in binding to that isoform in acompetitive binding assay.

[0037] If desired, antibodies specific for a particular isoform can beused to produce anti-idiotypic (paratope-specific) antibodies. See e.g.,McNamara et al., Science 220, 1325-26 (1984), R. C. Kennedy, et al.,Science 232, 220 (1986).

[0038] 3. Immunoassay Techniques.

[0039] Those skilled in the art will be familiar with numerous specificimmunoassay formats and variations thereof which may be useful forcarrying out the method disclosed herein. See generally E. Maggio,Enzyme-Immunoassay, (1980)(CRC Press, Inc., Boca Raton, Fla.); see alsoU.S. Pat. No. 4,727,022 to Skold et al. titled “Methods for ModulatingLigand-Receptor Interactions and their Application,” U.S. Pat. No.4,659,678 to Forrest et al. titled “Immunoassay of Antigens,” U.S. Pat.No. 4,376,110 to David et al., titled “Immunometric Assays UsingMonoclonal Antibodies,” U.S. Pat. No. 4,275,149 to Litman et al., titled“Macromolecular Environment Control in Specific Receptor Assays,” U.S.Pat. No. 4,233,402 to Maggio et al., titled “Reagents and MethodEmploying Channeling,” and U.S. Pat. No. 4,230,767 to Boguslaski et al.,titled “Heterogenous Specific Binding Assay Employing a Coenzyme asLabel.”

[0040] Antibodies as described herein may be coupled or conjugated to asolid support suitable for a diagnostic assay (e.g., beads, plates,slides or wells formed from materials such as latex or polystyrene) inaccordance with known techniques, such as precipitation. Antibodies asdescribed herein may likewise be coupled or conjugated to detectablegroups such as radiolabels (e.g., ³⁵S, ¹²⁵I, ¹³¹I), enzyme labels (e.g.,horseradish peroxidase, alkaline phosphatase), fluorescent labels (e.g.,fluorescein), chemiluminescent labels (e.g., acridinium groups,metalloporphyrins such as phthalocyanine dyes, luminol, etc.), metalatoms (e.g., technetium-99m), etc., in accordance with known techniques.See, e.g., U.S. Pat. No. 4,472,509 to Gansow (metal chelates tomonoclonal antibodies); U.S. Pat. No. 5,061,641 to Schochat et al.; andU.S. Pat. No. 4,861,869 to Nicoleotti et al. (radiolabelling proteins).

[0041] Immunoassays, or other types of assays to detect and/orquantitate the level of the isoform in samples as described below, maybe used in screening assays to detect pathologic states associated withaberrant levels of isoform expression (e.g., tumors, inflammatorystates), diagnostic studies, prognostic studies, or to monitor theprogression or diminution of isoform expression in correlation withdisease state.

[0042] Samples that may be collected for use in carrying out theimmunoassay may be tissue samples from the organ or tissue of interestwithin the subject, such tissue generally of most interest being thosetypes of tissues/cells that express differing amounts of isoform inpathologic states as compared to non-pathologic states, or biologicalfluids such as blood (including blood fractions such as blood plasma orblood serum), urine, cerebrospinal fluid, etc). Examples may includeoverexpression or aberrant expression of the isoform in various types ofmalignancies (e.g ovarian cancer, endometrial cancer, pancreatic cancer,breast cancer, urinary bladder cancer, lung cancer, etc.), as well asoverexpression or aberrant expression in other pathologic states.

[0043] A biological sample may be a cell sample, with an interveningculturing step being performed between the time the cell sample iscollected from the subject and the immunoassay is carried out on thebiological sample.

[0044] For immunohistological techniques, a tissue sample is collectedfrom the subject, and the presence or absence of binding of an antibodyof the invention is detected. The presence of binding of the antibody inan abnormal pattern or a pattern indicative of a tumor or cancerindicates the presence of a tumor or cancer in the subject from whichthe tissue sample is collected. The presence of the antigen in ametastatic tumor deposit can also be used to determine a likely sourceof the primary tumor. Any suitable immunohistology format may be used.The tissue sample may include patient biopsies, resections or cells forcytologic study. A similar technique to immunohistology is the use ofsimilar techniques to detect and/or phenotype cells in body fluids orother suspensions as is used for flow cytometric examination.

[0045] For in vivo diagnostic purposes the antibody according to theinvention is coupled to or provided with a suitable externallydetectable label, such as e.g. a radiolabel as described above or ametal atom (e.g., technetium-99m), and administered to a subject (e.g.,by intraveneous or intraarterial injection), in an amount sufficient toproduce an externally detectable signal, whereupon the possiblelocalized accumulation of antibody in the body is determined, with alocalized accumulation of the antibody (in a region other than thatwhich would ordinarily be expected for normal subjects or subjects freeof disease) indicating the present of a tumor in that subject.

[0046] 4. Nucleic acid assay techniques.

[0047] Detection of mRNAs specific to EpoR isoforms 1, 2, 3, 4, and 5may be carried out by any suitable technique, including but not limitedto using reverse transcriptase-polymerase chain reaction (RT-PCR)amplification with isoform-specific primers and Southern blot analysisof the resulting RT-PCR amplicons. For example, PolyA⁺ RNA may beisolated by any technique known by those skilled in the art frompatients patient cells and/or cancer cells, including but not limited tobreast, colon, lung, ovary, and prostate cells or cancer cells. Methodsfor RT-PCR amplification of the isolated RNA are known in the art andmay be carried out using EpoR isoform-specific primer pairs, preferablyas described below.

[0048] Oligonucleotide probes (or primers) that specifically bind to anucleic acid encoding an isoform as described above (including theopposite strands thereof), and pairs of probes (where at least onemember of the pair is specific for a nucleic acid encoding oneparticular isoform), are also an aspect of the present invention. Ingeneral, such probes are from 8 or 10 nucleic acids in length up to 40or 50 nucleic acids in length, or more. By “specifically bind” is meantthat a probe binds to a nucleic acid (or complement thereof) thatencodes one isoform as described herein, but does not bind to a nucleicacid (or complement thereof) that encodes another isoform as describedherein. Probes may optionally be labeled with a detectable group such asa radioisotope, enzyme, or member of a binding pair in some assayformats. Where a pair of probes or primers is used for amplification, itwill be appreciated that only one member of the pair need beisoform-specific, and that the other member of the pair may be one whichwill bind to nucleic acids encoding more than one of the isoformsdescribed herein, so long as the primer pair specifically amplifies onlynucleic acid encoding one of the isoforms described herein. Examples ofsuch oligonucleotide probes, and pairs thereof, are as follows: Primerpair specific for intron 6 insert (isoform 1) 28AS-: 5′ TCA AGC GGC TGCTTC CTT CCA A 3′ (SEQ ID NO: 14) ER4-5: 5′ GCA GGG AGC GTA CAG AGG GTGGAG 3′ (SEQ ID NO: 15) Primer pair specific for intron 7 insert (isoform2) 33AS: 5′ GAA GAA ATA GCA CCA ACC TGG AAG 3′ (SEQ ID NO: 16) 31S: 5′CTG ACG CCT AGC GAC CTG GAC C 3′ (SEQ ID NO: 17) Primer pair specificfor intron 7 unspliced (isoform 3) 31AS: 5′ GCA GTT TGG CTG CAA GAA GCA3′ (SEQ ID NO: 18) 31S: 5′ CTG ACG CCT AGC GAC CTG GAC C 3′ (SEQ ID NO:17) Primer pair specific for intron 5 unspliced (isoform 4) 26S: 5′ GGAGCC AGG GCG AAT CAC GG 3′ (SEQ ID NO: 19) 32S: 5′ GCC TTC AAA CTC GCTCTC TG 3′ (SEQ ID NO: 20) Primer pair specific for exon 6 skipped(isoform 5) 34AS 5′ GCT TCA GAG CCC GCT AGG CGT 3′ (SEQ ID NO: 21) ER4-55′ GCA GGG AGC GTA CAG AGG GTG GAG 3′ (SEQ ID NO: 15)

[0049] Note that, in the foregoing pairs, the primers of SEQ ID NO. 14,16, 18, 19 and 21 are specific for the identified isoform, and theprimers of SEQ ID NO. 15, 17 and 20 are not specific. In each pair, onlyone primer need be specific to provide an isoform-specific primer pair.

[0050] Blotting techniques are well known in the art. See, e.g.,Sambrook et al., Molecular Clooning: a Laboratory Manual 3rd Ed. (ColdSpring Harbor, N.Y.,); Ausubel et al. Current Protocols in MolecularBiology (Green Publishing Associates, Inc. and John Wiley & Sons, Inc.,New York). The nucleic acids resulting from RT-PCR amplification may beseparated by gel electrophoresis and immobilized on a suitable matrix,e.g. a filter of nitrocellulose. The presence of target sequences amongthe amplification products may be shown by incubation of the blottedamplicons with a probe (usually labeled) under conditions that promotedenaturation and rehybridization. Because the probe is designed to basepair with target sequences, the probe will bind under renaturingconditions. Unbound probe is then removed, and detection of targetsequences may be accomplished via known techniques to detect the labeledprobe.

[0051] The present invention and the various methods and compoundstherein are explained in greater detail in the following non-limitingexamples.

EXAMPLE 1

[0052] The Erythropoietin Receptor (EpoR) gene. The human EpoR gene hasbeen cloned and sequenced as previously described (Noguchi et al. (1991)Blood 78:2548-2556). The gene spans 8.6 kilobases, and comprises of 8exons with 7 intervening introns, the latter of which range in size from81 bp to 2.1 kb. The organization of the EpoR gene is outlined inFIG. 1. The full-length wild-type form of EpoR comprises of 508 aminoacids (SEQ ID NO: 2) in three domains: extracellular, transmembrane(TM), and cytoplasmic. Exons 1-5 encode for the extracellular domain ofEpoR, exon VI encodes for the transmembrane domain, while exons VII andVIII encode for the cytoplasmic domain of the receptor. In theexamination of EpoR expression in tumor vasculature, analysis by RT-PCRindicated a high level of EpoR mRNA expression in breast cancer cells,as well as squamous cell cancers of head-neck and uterine cervix wasobserved.

EXAMPLE 2

[0053] Novel Isoforms of EpoR mRNA Transcripts. The resulting RT-PCRamplification products derived from human cervix, breast, prostate, andovarian cancer cell lines were sequenced and analyzed. The results ofthis study revealed five alternatively spliced EpoR mRNA transcriptsthat differ from the mature, full-length wild-type EpoR mRNA. Usingisoform-specific PCR primers, transcripts corresponding to each isoformwere detected in breast, colon, lung, ovarian and prostate cancer. Theorganization of these five isoforms is outlined in FIG. 1. Thealternative forms of EpoR predicted to be coded for from thesealternatively spliced mRNAs fall into two categories. Isoforms 1, 2, and3 are described as truncated (EpoR-T), and possess the extracellular andtransmembrane domains of the wild-type receptor, while lacking portionsof the cytoplasmic domain. Isoforms 4 and 5 are described as soluble(EpoR-S), and only possess the extracellular domain of the wild-typereceptor intact. The changes in the putative C-terminal amino acidsequence encoded by these mRNAs are outlined in FIG. 2.

EXAMPLE 3

[0054] EpoR Isoform 1. The mRNA that codes for Isoform 1 contains anadditional 114 nucleotides from intron 6 (nucleotides 5949-6062, SEQ IDNO: 1) spliced between exons 6 and 7. The resulting mRNA will code foran EpoR peptide 285 amino acids in length (SEQ ID NO: 5) with a severetruncation in the cytoplasmic region. At the C-terminal, 9 novel aminoacids (M V R E G S R R R STOP) inserted at position 277 of thefull-length EpoR peptide sequence.

EXAMPLE 4

[0055] EpoR Isoform 2. The mRNA that codes for Isoform 2 is the resultof an alternative splicing event between the 3′ end of exon 7 and 5′ endof exon 8, in which an additional 19 nucleotides (nucleotides 7498-7516,SEQ ID NO: 1) are added to the 5′ end of exon 8. The mRNA from thissplicing event codes for an EpoR peptide 317 amino acids in length (SEQID NO: 7) with a severe truncation in the cytoplasmic domain, in which12 novel amino acids (V G A I S S A V A V P E STOP) are inserted atposition 306 of the EpoR peptide sequence. As with Isoform 1, Isoform 2also possesses a truncation of the cytoplasmic domain of the full-lengthpeptide sequence of EpoR.

EXAMPLE 5

[0056] EpoR Isoform 3. The translation of isoform 3 results from aprocessed EpoR mRNA in which sequences from intron 7 (nucleotides7422-7516, SEQ ID NO: 1) are not spliced out of the final message. Theresulting translation is a 328 amino acid peptide (SEQ ID NO: 9), with23 novel amino acids introduced to the C-terminus (V G G L V V P S V P GL P C F L Q P N C R P L STOP) at position 306 of the EpoR peptidesequence. As with Isoforms 1 and 2, Isoform 3 possesses a truncation ofthe cytoplasmic domain of the full-length peptide sequence of EpoR. Thesequence of the ORF of the mRNA message (SEQ ID NO: 8) and the peptidesequence of EpoR Isoform 3 (SEQ ID NO: 9) is identical to thetranslation predicted from an mRNA described previously (Nakamura et al.(1992) Science 257:1138-1141).

EXAMPLE 6

[0057] EpoR Isoform 4. The processed EpoR mRNA that translates intoIsoform 4 contains sequences from intron 5 (nucleotides 5061-5144, SEQID NO:1) are not spliced out of the final message. The resultingtranslation is a 267 amino acid peptide (SEQ ID NO:11) with 21 novelamino acids (G E A P G G G V G G A R A N H G A S P P P STOP) introducedto the C-terminus at position 247 of the full-length EpoR peptidesequence. This isoform of EpoR possesses neither the transmembrane norcytoplasmic domains of the full-length receptor. The translation thatcodes for Isoform 4 results in a soluble form of EpoR, containing theextracellular domain of the receptor only.

EXAMPLE 7

[0058] EpoR Isoform 5. Isoform 6 is a translation that results from thealternatively processed EpoR mRNA in which sequences from exon 6 areskipped, i.e. exons 5 and 7 are spliced together directly. Thetranslation of this message results in a 248 amino acid peptide (SEQ IDNO:13), in which 2 novel amino acids (G L STOP) are introduced atposition 247 of the full-length peptide sequence of EpoR. As withIsoform 4, isoform 5 of EpoR is a soluble form of the receptor thatcomprises of only the extracellular domain.

[0059] The foregoing is illustrative of the present invention, and isnot to be construed as limiting thereof. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

1 21 1 8647 DNA Homo sapiens CDS (1916)..(2030) exon 1 1 ggatccacccacctcggcct cccaaagtgc tgggattaca ggcatgagca ctgtgcatgg 60 actatttatttatttttttg aaacagagtt tcaatcttgt tgcacagcct ggagtgcaat 120 ggtgtgatctcagctcactg caacctctgc cttctggttt caagcaattc tcctgcctca 180 gcctcctgagtagctgggat tacaggcacc caccaccacg ctcgaatata tatatatatt 240 ttttgagacggagtccgctc tgtcaccagg ctggagtgca gtggccaaat atcggctcac 300 tgaaacctccggctcctggg ttcaagcgat tctcctgcag cctcccaagt agctgggatt 360 acaggcatgcagcaccacgc ccatctaatt tttgtatttt tggtagagat ggggttttac 420 catgttggccaggatggtct tgatctcttg acctcgtgat ctgcccacct cggcctccca 480 aagtgctgggattacaggcg tgacgaccgc gcccggccta cgcctggcta atttttgtat 540 ttttagtagagacgtggttt cgccatgttg cccaggctgg tctcgaactc ctgacctcat 600 gatccgcctgtctcggcctc ccaaagtgtt gggattacaa gtatgagcca ccgcgccact 660 agccaattttttttattttt tgagatgcag tctcactctg ttgcccaggc tggagttgca 720 gtggcatgatcttggctcac tgcaatcttc atctcccaga ctgaagcagt tctcatgcct 780 cagcctcctgagtagctggg attacagcac acgccaccac acctggctaa tttttgtatt 840 tttagtagagatgggatttc accatgttgg ccaggctggt ctcaaactcc tgacctcaag 900 tgatttgcccacgtcggcct cccaaagtgc tgggattata ggcgtgagcc accgcccagc 960 ccaagagaataaaaatgtgg gtggtaaaaa tttttttccc aaaaattcgt aaatgaaaat 1020 ctcacatattatgcatactg cccaggagca tggcctagca ctgtgcaaac actcaactgc 1080 tggtcgttgcaaggattatt attggccggc ttcagtggct tgctggtatt cccagcacat 1140 tgggagatggaggctggagg attgcttaag tccgggattt caagaccagc ctggacaaca 1200 tagtgggatcccatctctac aaagaatttt aaaaattagc caggtgcagt gggaagattg 1260 cttcagtccagaggctgcag tgagctatga ttgtgccact gcactccagc ctgggtgaca 1320 gagcaacaccctgagacaga gagagagagg gggaaggagg gaaggaggga aggaaggaag 1380 gaaggaaggaaggaaggaag gaaggaagga aggaaggaaa ggagagagag agagagagag 1440 agagagagagagagagaaaa taatttttat ttatttccag gctgggaaga gatgctgatt 1500 tctgcgataaaatcagtagg tacatttttt ggaatgttcg ctatgtgcca ggctagattt 1560 tacagatgagaagtctgaag ctcaggtaag gtaagtcacc tgtccagggc cacaaagaaa 1620 aaaaaaacgtgtgtctgaag ccagaacggg agctgttgcg cccaactccc tcccctgccc 1680 ccaagcggcctctgggctcg ggaagggccc ctgcctcctc ccgccaggca cttatctcta 1740 cccaggctgagtgctggccc cgcccctcgg ggatctgcca cttagaggcg cctggtcggg 1800 aagggcctggtcagctgcgt ccggcggagg cagctgctga cccagctgtg gactgtgccg 1860 ggggtgggggacggaggggc aggagccctg ggctccccgt ggcgggggct gtatc atg 1918 Met 1 gac cacctc ggg gcg tcc ctc tgg ccc cag gtc ggc tcc ctt tgt ctc 1966 Asp His LeuGly Ala Ser Leu Trp Pro Gln Val Gly Ser Leu Cys Leu 5 10 15 ctg ctc gctggg gcc gcc tgg gcg ccc ccg cct aac ctc ccg gac ccc 2014 Leu Leu Ala GlyAla Ala Trp Ala Pro Pro Pro Asn Leu Pro Asp Pro 20 25 30 aag ttc gag agcaaa g gtaaggatga gctgcgtgtg gacccctacg ctggagcctg 2070 Lys Phe Glu SerLys 35 caggaccatg ctggggcctg aactcccagc ctaggtcctg ggggccatgc tgtttctgga2130 cttcctgacc gggtcctggg ggccaagctg gcatctgaac ccttagactg ggtcctggat2190 gggtgggggg cggggtgggg tatgttagga tccaagactc ctgatcgcgt cccgggcaag2250 agctagagtg ggcttaacat tcccgtttta ccttttcagg gagtctggga catgctaaat2310 cctaaggggg ctgacttggt gctaaggtcc ctggggggtg gggaccaagc cgatccctag2370 gggagggagg gtaaagcccg ggtccgagtt agagggccaa gccacaggct actgtaaaca2430 cggtttgtgt gagggcgcca gatcacttgc ccggcccggt ggagggaggg aggcgggggg2490 cacggttggc gctatcggtt ggcggggagc ctgccggggc cgataggggg cccgcctctc2550 cgcacacacc cccagccgcg cgcgtgtcct aggctggggc ggggctggca gtcccgagct2610 cgaggtcttg aacgccgcgc ccagctcagc tggccgctgg gtgggcaggt gtgcgccagt2670 ggtgcacggc gggggacagt aaggcgagaa acttgcccct gggaattagg ggggcaccac2730 ctctgcggac ccctccaagg gacccgcttg ggaagatggc agggcggggc ttttttctta2790 tcgggtccgc ccaggctgcg ggagggaaga ggagggggct gtctcccgag gatagagctc2850 agacccccat gcccttcctt tgtcgcccct ccccag cg gcc ttg ctg gcg gcc 2903Ala Ala Leu Leu Ala Ala 40 cgg ggg ccc gaa gag ctt ctg tgc ttc acc gagcgg ttg gag gac ttg 2951 Arg Gly Pro Glu Glu Leu Leu Cys Phe Thr Glu ArgLeu Glu Asp Leu 45 50 55 60 gtg tgt ttc tgg gag gaa gcg gcg agc gct ggggtg ggc ccg ggc aac 2999 Val Cys Phe Trp Glu Glu Ala Ala Ser Ala Gly ValGly Pro Gly Asn 65 70 75 tac agc ttc tcc tac cag ctc ga gtgagtccgatccggcgggt gcctccaagg 3052 Tyr Ser Phe Ser Tyr Gln Leu Glu 80 gcggagggagggggtggggc agagctccct ggaggtcgta gcctcgtatg tcccctgctg 3112 tttgaggcccgacggcgcct ccagtcgtgg tcactggagg gaaacctgcg ggtccagggc 3172 tggcacgcctctatgggccg gggcgcgaac actcccgcga tcaccgctgg aacgcgaccc 3232 caaacatcaggctgggataa caacgcctcc aaatcgaggg taaggcgtta ctacgtcggg 3292 gctgggacgccttctcgagg tagtatccaa aaggaggcca gcagtgctca tgcctgtaat 3352 cccaactctttggaaggtcg agcggaagaa ccgcttgagc ccaggtgttc aagaccagcc 3412 tgggcaacacagcgagatcc ccgtctctta aaaaaaaatt agactgggcg cggctgcacg 3472 cctgtaatcccagcactttg ggaggctgag gcgggcggat cacctgaggt cgggagtttg 3532 agagccagcctggccaacat ggagaaactc tatctctact aaaaatacaa aattagccgg 3592 gcgtggtggcgcatgcctgt gatcccagct actcgggagg ctgaggcagg agaatcgctt 3652 gaacccgggaggcggaggtt gcggtgagcc gaggtagcgc cattgcactc cagcctgggc 3712 aacaagagcgaaactccgtc tcaaaaaaaa aaaaaataaa agccaggcgt ggcgcgtgcc 3772 tgtggtctcaactacttggg aagctgaggt gggaggatcc cttaagcccc agaatttgag 3832 gctgcagtgagccatgatcg cgccactgca ctccagcctg ggcgacgaag gaacaccttg 3892 tcacacacacacacaaggct agaccttgtg tcacacatac acactgcccc ccacaggccg 3952 ggcaatgccaactccccggt cccccctccc aacctgctcc cttccctggg cgcatag g 4010 gat gag ccatgg aag ctg tgt cgc ctg cac cag gct ccc acg gct cgt 4058 Asp Glu Pro TrpLys Leu Cys Arg Leu His Gln Ala Pro Thr Ala Arg 85 90 95 100 ggt gcg gtgcgc ttc tgg tgt tcg ctg cct aca gcc gac acg tcg agc 4106 Gly Ala Val ArgPhe Trp Cys Ser Leu Pro Thr Ala Asp Thr Ser Ser 105 110 115 ttc gtg ccccta gag ttg cgc gtc aca gca gcc tcc ggc gct ccg cga 4154 Phe Val Pro LeuGlu Leu Arg Val Thr Ala Ala Ser Gly Ala Pro Arg 120 125 130 tat cac cgtgtc atc cac atc aat gaa gta g gtaagtgctc tgggaatgga 4205 Tyr His Arg ValIle His Ile Asn Glu Val 135 140 ggagtggtcg gaggagaggg tctcagtcctcgcccacctg accaaccccc atgcctgcag 4265 tg ctc cta gac gcc ccc gtg ggg ctggtg gcg cgg ttg gct gac gag 4312 Val Leu Leu Asp Ala Pro Val Gly Leu ValAla Arg Leu Ala Asp Glu 145 150 155 agc ggc cac gta gtg ttg cgc tgg ctcccg ccg cct gag aca ccc atg 4360 Ser Gly His Val Val Leu Arg Trp Leu ProPro Pro Glu Thr Pro Met 160 165 170 acg tct cac atc cgc tac gag gtg gacgtc tcg gcc ggc aac ggc gca 4408 Thr Ser His Ile Arg Tyr Glu Val Asp ValSer Ala Gly Asn Gly Ala 175 180 185 190 ggg agc gta cag agg gtgaggccagcccctacggc ccagccccca aagctccact 4463 Gly Ser Val Gln Arg 195 gactacggcccagccacgcc tctcgaggtc gcgcccggtg ccgctttcag ggccggtccg 4523 taacatcccacatcccatta ccctggtgct gaagaccgtt ccacgcccac agacacagcc 4583 ccctttcctaatgtcctcgc aagcctgttg aaccccaact tcttctccct ccggcccgta 4643 accctagacccctttagcgc ccgggtccct ctacgagtgc tagcccagat attaaattgc 4703 ccgggtcccgccctttcgta ccagagactc tctctctgat tggccctgag ctttcttggg 4763 ctcctccccctactcttatt ggtcccattg caattctagg gcaccgtttt cctttcccct 4823 gattggctcagttccaccag ggcccgcccc cacgtcatct atttttgtct gctacgcgtc 4883 cctcgccctgattccgcccc cag gtg gag atc ctg gag ggc cgc acc gag tgt 4936 Val Glu IleLeu Glu Gly Arg Thr Glu Cys 200 205 gtg ctg agc aac ctg cgg ggc cgg acgcgc tac acc ttc gcc gtc cgc 4984 Val Leu Ser Asn Leu Arg Gly Arg Thr ArgTyr Thr Phe Ala Val Arg 210 215 220 gcg cgt atg gct gag ccg agc ttc ggcggc ttc tgg agc gcc tgg tcg 5032 Ala Arg Met Ala Glu Pro Ser Phe Gly GlyPhe Trp Ser Ala Trp Ser 225 230 235 gag cct gtg tcg ctg ctg acg cct agcg gtgaggcccc aggcgggggt 5080 Glu Pro Val Ser Leu Leu Thr Pro Ser 240 245gtaggaggag ccagggcgaa tcacggggca agcccaccgc cctgacctcc tccccgcctc 5140ttag ac ctg gac ccc ctc atc ctg acg ctc tcc ctc atc ctc gtg gtc 5188 AspLeu Asp Pro Leu Ile Leu Thr Leu Ser Leu Ile Leu Val Val 250 255 260 atcctg gtg ctg ctg acc gtg ctc gcg ctg ctc tcc cac cgc cg 5232 Ile Leu ValLeu Leu Thr Val Leu Ala Leu Leu Ser His Arg Arg 265 270 275 gtgagctccccatttgggcg ctgggcccag actcctcccc gccaacggtc ctctttcact 5292 atggaaacctaggctcagag agagacacgc acttgcccaa ggtcacgcag taaggattca 5352 catcagtggcagggctggga tgcatgccag actagaccca gactcttcgt taacattttc 5412 tgctcttggggactttcacc tgattttcct tctacatcag gggctgccat ttcttgggtc 5472 cctttgttagttcctttccc cagtgtcatc acctttgtaa aatcaactag atggatttag 5532 tgaaagaatttaagaccctg aatgcctccg cacccctgcg gtcaagcttc tcagacacta 5592 tgatcagactagccgttctg aggtatttgt aattccaagc acacactagg tggtttcaca 5652 cccccaagcttttgcccatg ctgttccctc tgcctggaat gcccttcctg ccttgtctgc 5712 taagcaatcttctagtcgtc tttcatggcc ctgttcattt acttggttgg aaaatacaaa 5772 cagagtgccaaacatgtgcc aggcactgga gagagaatgg agaacaagct agaccctgac 5832 cacaagtccctgaccttgtg gatctcaagt caacaaacaa gggacccaag aaatatttga 5892 tgacaaattgtaatgagtga tatcacagaa acaaacagaa tgtggtgaca tgacaggatg 5952 gtcagggaaggctccaggag gaggtgacat cagagtggaa acctgaagat tggaaggaag 6012 cagccgcttgaaaagtgggg agaagaaaca gcaagtgcaa aggccctgag gtgggaatga 6072 gattggaacgttcagccagc ttcaagaatt gccacatgca tggcctggca tggtggctca 6132 cgcctgtaatcccagcactt tgggatgccg aggcaggcag atcacctgag gttgggagtt 6192 cgcgaccagcctgaccaaca tggagaaacc ccacctctac taaaaataca aaactagcca 6252 agcgtggtggcacatgcctg taatccccgc tactcgggag gctgaggcag gagaatcact 6312 tgaacctgggaggtggaggt tgcgggtgag ccgagatcgt gccatcgcat tccagcctgg 6372 gcaataagagtgaaactccg tctcaaaaaa aaaaaaaaaa ttgccacatg gctagagtgg 6432 tatgtaagggggtgtggcag atattgagat gagggaggtg acaggggtca tataacgcag 6492 ggccttctgcagggtggtgg ggaggagttt ggaatttttt ttttttttga gacagagtca 6552 ctcttgtcgcccaagctgta gtgcagtgca gcagtcttgg ctcactgcaa ctctgcctcc 6612 caggttcaagtgattctcct gcctcaaccg cctgagtagc tgagattaca ggcgtgcatg 6672 cccggctaattttgtagttt tagtagagac ggggttccac catgttggcc aggctggtct 6732 caaactcctgacctcaggtg atctgctcac atcagcctct caaagtgctg ggattatagg 6792 catgagccaccgtgcctggc ttggatttta tcctaaatgc ctctctcatt accccagaag 6852 gtaacataatatttatctat gaagtgacat catggacctc ctggaaaaat ctgggccagg 6912 gttttgggttttttaattta ttttatttta ttttttttag agatgggggt ctcactatgt 6972 ttcctaggctggtcttgaac tcctgggttc aaatgatcct cccacctcag cctcccaaag 7032 tactgggattatagtgctgg tgtaaaccac tgcacctggc catggccagg attaaaggga 7092 gaatgaccaaggtatattga actcctatgc acccttcaat accctgttcc atttaccctt 7152 ttgtagggccttgctgatgc ttcagccaaa acccctgtcc cctggccctg atgtactcct 7212 ctgcctccattgtgatcaca gggaccaagt gtatctgtgc ctctatgact gggagtggag 7272 ggggaattggtgagtattca atgagtcata tctatgtaac tatttatatt ggcttcaaca 7332 g g gct ctgaag cag aag atc tgg cct ggc atc ccg agc cca gag agc 7379 Ala Leu Lys GlnLys Ile Trp Pro Gly Ile Pro Ser Pro Glu Ser 280 285 290 gag ttt gaa ggcctc ttc acc acc cac aag ggt aac ttc cag 7421 Glu Phe Glu Gly Leu Phe ThrThr His Lys Gly Asn Phe Gln 295 300 305 gtaggtggcc tggttgtccc ctcagtgcctgggcttccct gcttcttgca gccaaactgc 7481 aggcctctct gagcaggttg gtgctatttcttcag ctg tgg ctg tac cag aat 7534 Leu Trp Leu Tyr Gln Asn 310 gat ggctgc ctg tgg tgg agc ccc tgc acc ccc ttc acg gag gac cca 7582 Asp Gly CysLeu Trp Trp Ser Pro Cys Thr Pro Phe Thr Glu Asp Pro 315 320 325 cct gcttcc ctg gaa gtc ctc tca gag cgc tgc tgg ggg acg atg cag 7630 Pro Ala SerLeu Glu Val Leu Ser Glu Arg Cys Trp Gly Thr Met Gln 330 335 340 gca gtggag ccg ggg aca gat gat gag ggc ccc ctg ctg gag cca gtg 7678 Ala Val GluPro Gly Thr Asp Asp Glu Gly Pro Leu Leu Glu Pro Val 345 350 355 ggc agtgag cat gcc cag gat acc tat ctg gtg ctg gac aaa tgg ttg 7726 Gly Ser GluHis Ala Gln Asp Thr Tyr Leu Val Leu Asp Lys Trp Leu 360 365 370 375 ctgccc cgg aac ccg ccc agt gag gac ctc cca ggg cct ggt ggc agt 7774 Leu ProArg Asn Pro Pro Ser Glu Asp Leu Pro Gly Pro Gly Gly Ser 380 385 390 gtggac ata gtg gcc atg gat gaa ggc tca gaa gca tcc tcc tgc tca 7822 Val AspIle Val Ala Met Asp Glu Gly Ser Glu Ala Ser Ser Cys Ser 395 400 405 tctgct ttg gcc tcg aag ccc agc cca gag gga gcc tct gct gcc agc 7870 Ser AlaLeu Ala Ser Lys Pro Ser Pro Glu Gly Ala Ser Ala Ala Ser 410 415 420 tttgag tac act atc ctg gac ccc agc tcc cag ctc ttg cgt cca tgg 7918 Phe GluTyr Thr Ile Leu Asp Pro Ser Ser Gln Leu Leu Arg Pro Trp 425 430 435 acactg tgc cct gag ctg ccc cct acc cca ccc cac cta aag tac ctg 7966 Thr LeuCys Pro Glu Leu Pro Pro Thr Pro Pro His Leu Lys Tyr Leu 440 445 450 455tac ctt gtg gta tct gac tct ggc atc tca act gac tac agc tca ggg 8014 TyrLeu Val Val Ser Asp Ser Gly Ile Ser Thr Asp Tyr Ser Ser Gly 460 465 470gac tcc cag gga gcc caa ggg ggc tta tcc gat ggc ccc tac tcc aac 8062 AspSer Gln Gly Ala Gln Gly Gly Leu Ser Asp Gly Pro Tyr Ser Asn 475 480 485cct tat gag aac agc ctt atc cca gcc gct gag cct ctg ccc ccc agc 8110 ProTyr Glu Asn Ser Leu Ile Pro Ala Ala Glu Pro Leu Pro Pro Ser 490 495 500tat gtg gct tgc tct taggacacca ggctgcagat gatcagggat ccaatatgac 8165 TyrVal Ala Cys Ser 505 tcagagaacc agtgcagact caagacttat ggaacagggatggcgaggcc tctctcagga 8225 gcaggggcat tgctgatttt gtctgcccaa tccatcctgctcaggaaacc acaaccttgc 8285 agtattttta aatatgtata gttttttttt gtatctatatatatatatac acatatgtat 8345 gtaagttttt ctaccatgat ttctacaaac accctttaagtcccatcttc ccctgggcat 8405 aggccatagg gatagaagtt aaagttcttg agcttattcagaagctggat ctgcaatctg 8465 aatgctactc ataacataac aaaatagtat gttaaacagctcttaaatct tactggctta 8525 ccacattaaa tgatttctct ctcctaactc agctcaaatgggcagccatc catggatgag 8585 tcagaggttc agactcttcc agtctgtagc tctaccttctcttagggtac ttagatggat 8645 cc 8647 2 508 PRT Homo sapiens 2 Met Asp HisLeu Gly Ala Ser Leu Trp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 Leu LeuLeu Ala Gly Ala Ala Trp Ala Pro Pro Pro Asn Leu Pro Asp 20 25 30 Pro LysPhe Glu Ser Lys Ala Ala Leu Leu Ala Ala Arg Gly Pro Glu 35 40 45 Glu LeuLeu Cys Phe Thr Glu Arg Leu Glu Asp Leu Val Cys Phe Trp 50 55 60 Glu GluAla Ala Ser Ala Gly Val Gly Pro Gly Asn Tyr Ser Phe Ser 65 70 75 80 TyrGln Leu Glu Asp Glu Pro Trp Lys Leu Cys Arg Leu His Gln Ala 85 90 95 ProThr Ala Arg Gly Ala Val Arg Phe Trp Cys Ser Leu Pro Thr Ala 100 105 110Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg Val Thr Ala Ala Ser 115 120125 Gly Ala Pro Arg Tyr His Arg Val Ile His Ile Asn Glu Val Val Leu 130135 140 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu Ala Asp Glu Ser Gly145 150 155 160 His Val Val Leu Arg Trp Leu Pro Pro Pro Glu Thr Pro MetThr Ser 165 170 175 His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn GlyAla Gly Ser 180 185 190 Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr GluCys Val Leu Ser 195 200 205 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe AlaVal Arg Ala Arg Met 210 215 220 Ala Glu Pro Ser Phe Gly Gly Phe Trp SerAla Trp Ser Glu Pro Val 225 230 235 240 Ser Leu Leu Thr Pro Ser Asp LeuAsp Pro Leu Ile Leu Thr Leu Ser 245 250 255 Leu Ile Leu Val Val Ile LeuVal Leu Leu Thr Val Leu Ala Leu Leu 260 265 270 Ser His Arg Arg Ala LeuLys Gln Lys Ile Trp Pro Gly Ile Pro Ser 275 280 285 Pro Glu Ser Glu PheGlu Gly Leu Phe Thr Thr His Lys Gly Asn Phe 290 295 300 Gln Leu Trp LeuTyr Gln Asn Asp Gly Cys Leu Trp Trp Ser Pro Cys 305 310 315 320 Thr ProPhe Thr Glu Asp Pro Pro Ala Ser Leu Glu Val Leu Ser Glu 325 330 335 ArgCys Trp Gly Thr Met Gln Ala Val Glu Pro Gly Thr Asp Asp Glu 340 345 350Gly Pro Leu Leu Glu Pro Val Gly Ser Glu His Ala Gln Asp Thr Tyr 355 360365 Leu Val Leu Asp Lys Trp Leu Leu Pro Arg Asn Pro Pro Ser Glu Asp 370375 380 Leu Pro Gly Pro Gly Gly Ser Val Asp Ile Val Ala Met Asp Glu Gly385 390 395 400 Ser Glu Ala Ser Ser Cys Ser Ser Ala Leu Ala Ser Lys ProSer Pro 405 410 415 Glu Gly Ala Ser Ala Ala Ser Phe Glu Tyr Thr Ile LeuAsp Pro Ser 420 425 430 Ser Gln Leu Leu Arg Pro Trp Thr Leu Cys Pro GluLeu Pro Pro Thr 435 440 445 Pro Pro His Leu Lys Tyr Leu Tyr Leu Val ValSer Asp Ser Gly Ile 450 455 460 Ser Thr Asp Tyr Ser Ser Gly Asp Ser GlnGly Ala Gln Gly Gly Leu 465 470 475 480 Ser Asp Gly Pro Tyr Ser Asn ProTyr Glu Asn Ser Leu Ile Pro Ala 485 490 495 Ala Glu Pro Leu Pro Pro SerTyr Val Ala Cys Ser 500 505 3 1865 DNA Homo sapiens misc_feature(1)..(1865) Mature full-length EpoR mRNA 3 acttagaggc gcctggtcgggaagggcctg gtcagctgcg tccggcggag gcagctgctg 60 acccagctgt ggactgtgccgggggtgggg gacggagggg caggagccct gggctccccg 120 tggcgggggc tgtatcatggaccacctcgg ggcgtccctc tggccccagg tcggctccct 180 ttgtctcctg ctcgctggggccgcctgggc gcccccgcct aacctcccgg accccaagtt 240 cgagagcaaa gcggccttgctggcggcccg ggggcccgaa gagcttctgt gcttcaccga 300 gcggttggag gacttggtgtgtttctggga ggaagcggcg agcgctgggg tgggcccggg 360 caactacagc ttctcctaccagctcgagga tgagccatgg aagctgtgtc gcctgcacca 420 ggctcccacg gctcgtggtgcggtgcgctt ctggtgttcg ctgcctacag ccgacacgtc 480 gagcttcgtg cccctagagttgcgcgtcac agcagcctcc ggcgctccgc gatatcaccg 540 tgtcatccac atcaatgaagtagtgctcct agacgccccc gtggggctgg tggcgcggtt 600 ggctgacgag agcggccacgtagtgttgcg ctggctcccg ccgcctgaga cacccatgac 660 gtctcacatc cgctacgaggtggacgtctc ggccggcaac ggcgcaggga gcgtacagag 720 ggtggagatc ctggagggccgcaccgagtg tgtgctgagc aacctgcggg gccggacgcg 780 ctacaccttc gccgtccgcgcgcgtatggc tgagccgagc ttcggcggct tctggagcgc 840 ctggtcggag cctgtgtcgctgctgacgcc tagcgacctg gaccccctca tcctgacgct 900 ctccctcatc ctcgtggtcatcctggtgct gctgaccgtg ctcgcgctgc tctcccaccg 960 ccgggctctg aagcagaagatctggcctgg catcccgagc ccagagagcg agtttgaagg 1020 cctcttcacc acccacaagggtaacttcca gctgtggctg taccagaatg atggctgcct 1080 gtggtggagc ccctgcacccccttcacgga ggacccacct gcttccctgg aagtcctctc 1140 agagcgctgc tgggggacgatgcaggcagt ggagccgggg acagatgatg agggccccct 1200 gctggagcca gtgggcagtgagcatgccca ggatacctat ctggtgctgg acaaatggtt 1260 gctgccccgg aacccgcccagtgaggacct cccagggcct ggtggcagtg tggacatagt 1320 ggccatggat gaaggctcagaagcatcctc ctgctcatct gctttggcct cgaagcccag 1380 cccagaggga gcctctgctgccagctttga gtacactatc ctggacccca gctcccagct 1440 cttgcgtcca tggacactgtgccctgagct gccccctacc ccaccccacc taaagtacct 1500 gtaccttgtg gtatctgactctggcatctc aactgactac agctcagggg actcccaggg 1560 agcccaaggg ggcttatccgatggccccta ctccaaccct tatgagaaca gccttatccc 1620 agccgctgag cctctgccccccagctatgt ggcttgctct taggacacca ggctgcagat 1680 gatcagggat ccaatatgactcagagaacc agtgcagact caagacttat ggaacaggga 1740 tggcgaggcc tctctcaggagcaggggcat tgctgatttt gtctgcccaa tccatcctgc 1800 tcaggaaacc acaaccttgcagtattttta aatatgtata gtttttttat atgtatagtt 1860 ttttt 1865 4 858 DNAHomo sapiens CDS (1)..(855) EpoR Isoform 1, intron 6 insert 4 atg gaccac ctc ggg gcg tcc ctc tgg ccc cag gtc ggc tcc ctt tgt 48 Met Asp HisLeu Gly Ala Ser Leu Trp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 ctc ctgctc gct ggg gcc gcc tgg gcg ccc ccg cct aac ctc ccg gac 96 Leu Leu LeuAla Gly Ala Ala Trp Ala Pro Pro Pro Asn Leu Pro Asp 20 25 30 ccc aag ttcgag agc aaa gcg gcc ttg ctg gcg gcc cgg ggg ccc gaa 144 Pro Lys Phe GluSer Lys Ala Ala Leu Leu Ala Ala Arg Gly Pro Glu 35 40 45 gag ctt ctg tgcttc acc gag cgg ttg gag gac ttg gtg tgt ttc tgg 192 Glu Leu Leu Cys PheThr Glu Arg Leu Glu Asp Leu Val Cys Phe Trp 50 55 60 gag gaa gcg gcg agcgct ggg gtg ggc ccg ggc aac tac agc ttc tcc 240 Glu Glu Ala Ala Ser AlaGly Val Gly Pro Gly Asn Tyr Ser Phe Ser 65 70 75 80 tac cag ctc gag gatgag cca tgg aag ctg tgt cgc ctg cac cag gct 288 Tyr Gln Leu Glu Asp GluPro Trp Lys Leu Cys Arg Leu His Gln Ala 85 90 95 ccc acg gct cgt ggt gcggtg cgc ttc tgg tgt tcg ctg cct aca gcc 336 Pro Thr Ala Arg Gly Ala ValArg Phe Trp Cys Ser Leu Pro Thr Ala 100 105 110 gac acg tcg agc ttc gtgccc cta gag ttg cgc gtc aca gca gcc tcc 384 Asp Thr Ser Ser Phe Val ProLeu Glu Leu Arg Val Thr Ala Ala Ser 115 120 125 ggc gct ccg cga tat caccgt gtc atc cac atc aat gaa gta gtg ctc 432 Gly Ala Pro Arg Tyr His ArgVal Ile His Ile Asn Glu Val Val Leu 130 135 140 cta gac gcc ccc gtg gggctg gtg gcg cgg ttg gct gac gag agc ggc 480 Leu Asp Ala Pro Val Gly LeuVal Ala Arg Leu Ala Asp Glu Ser Gly 145 150 155 160 cac gta gtg ttg cgctgg ctc ccg ccg cct gag aca ccc atg acg tct 528 His Val Val Leu Arg TrpLeu Pro Pro Pro Glu Thr Pro Met Thr Ser 165 170 175 cac atc cgc tac gaggtg gac gtc tcg gcc ggc aac ggc gca ggg agc 576 His Ile Arg Tyr Glu ValAsp Val Ser Ala Gly Asn Gly Ala Gly Ser 180 185 190 gta cag agg gtg gagatc ctg gag ggc cgc acc gag tgt gtg ctg agc 624 Val Gln Arg Val Glu IleLeu Glu Gly Arg Thr Glu Cys Val Leu Ser 195 200 205 aac ctg cgg ggc cggacg cgc tac acc ttc gcc gtc cgc gcg cgt atg 672 Asn Leu Arg Gly Arg ThrArg Tyr Thr Phe Ala Val Arg Ala Arg Met 210 215 220 gct gag ccg agc ttcggc ggc ttc tgg agc gcc tgg tcg gag cct gtg 720 Ala Glu Pro Ser Phe GlyGly Phe Trp Ser Ala Trp Ser Glu Pro Val 225 230 235 240 tcg ctg ctg acgcct agc gac ctg gac ccc ctc atc ctg acg ctc tcc 768 Ser Leu Leu Thr ProSer Asp Leu Asp Pro Leu Ile Leu Thr Leu Ser 245 250 255 ctc atc ctc gtggtc atc ctg gtg ctg ctg acc gtg ctc gcg ctg ctc 816 Leu Ile Leu Val ValIle Leu Val Leu Leu Thr Val Leu Ala Leu Leu 260 265 270 tcc cac cgc cggatg gtc agg gaa ggc tcc agg agg agg tga 858 Ser His Arg Arg Met Val ArgGlu Gly Ser Arg Arg Arg 275 280 285 5 285 PRT Homo sapiens 5 Met Asp HisLeu Gly Ala Ser Leu Trp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 Leu LeuLeu Ala Gly Ala Ala Trp Ala Pro Pro Pro Asn Leu Pro Asp 20 25 30 Pro LysPhe Glu Ser Lys Ala Ala Leu Leu Ala Ala Arg Gly Pro Glu 35 40 45 Glu LeuLeu Cys Phe Thr Glu Arg Leu Glu Asp Leu Val Cys Phe Trp 50 55 60 Glu GluAla Ala Ser Ala Gly Val Gly Pro Gly Asn Tyr Ser Phe Ser 65 70 75 80 TyrGln Leu Glu Asp Glu Pro Trp Lys Leu Cys Arg Leu His Gln Ala 85 90 95 ProThr Ala Arg Gly Ala Val Arg Phe Trp Cys Ser Leu Pro Thr Ala 100 105 110Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg Val Thr Ala Ala Ser 115 120125 Gly Ala Pro Arg Tyr His Arg Val Ile His Ile Asn Glu Val Val Leu 130135 140 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu Ala Asp Glu Ser Gly145 150 155 160 His Val Val Leu Arg Trp Leu Pro Pro Pro Glu Thr Pro MetThr Ser 165 170 175 His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn GlyAla Gly Ser 180 185 190 Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr GluCys Val Leu Ser 195 200 205 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe AlaVal Arg Ala Arg Met 210 215 220 Ala Glu Pro Ser Phe Gly Gly Phe Trp SerAla Trp Ser Glu Pro Val 225 230 235 240 Ser Leu Leu Thr Pro Ser Asp LeuAsp Pro Leu Ile Leu Thr Leu Ser 245 250 255 Leu Ile Leu Val Val Ile LeuVal Leu Leu Thr Val Leu Ala Leu Leu 260 265 270 Ser His Arg Arg Met ValArg Glu Gly Ser Arg Arg Arg 275 280 285 6 954 DNA Homo sapiens CDS(1)..(951) EpoR Isoform 2, intron 7 insert 6 atg gac cac ctc ggg gcg tccctc tgg ccc cag gtc ggc tcc ctt tgt 48 Met Asp His Leu Gly Ala Ser LeuTrp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 ctc ctg ctc gct ggg gcc gcctgg gcg ccc ccg cct aac ctc ccg gac 96 Leu Leu Leu Ala Gly Ala Ala TrpAla Pro Pro Pro Asn Leu Pro Asp 20 25 30 ccc aag ttc gag agc aaa gcg gccttg ctg gcg gcc cgg ggg ccc gaa 144 Pro Lys Phe Glu Ser Lys Ala Ala LeuLeu Ala Ala Arg Gly Pro Glu 35 40 45 gag ctt ctg tgc ttc acc gag cgg ttggag gac ttg gtg tgt ttc tgg 192 Glu Leu Leu Cys Phe Thr Glu Arg Leu GluAsp Leu Val Cys Phe Trp 50 55 60 gag gaa gcg gcg agc gct ggg gtg ggc ccgggc aac tac agc ttc tcc 240 Glu Glu Ala Ala Ser Ala Gly Val Gly Pro GlyAsn Tyr Ser Phe Ser 65 70 75 80 tac cag ctc gag gat gag cca tgg aag ctgtgt cgc ctg cac cag gct 288 Tyr Gln Leu Glu Asp Glu Pro Trp Lys Leu CysArg Leu His Gln Ala 85 90 95 ccc acg gct cgt ggt gcg gtg cgc ttc tgg tgttcg ctg cct aca gcc 336 Pro Thr Ala Arg Gly Ala Val Arg Phe Trp Cys SerLeu Pro Thr Ala 100 105 110 gac acg tcg agc ttc gtg ccc cta gag ttg cgcgtc aca gca gcc tcc 384 Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg ValThr Ala Ala Ser 115 120 125 ggc gct ccg cga tat cac cgt gtc atc cac atcaat gaa gta gtg ctc 432 Gly Ala Pro Arg Tyr His Arg Val Ile His Ile AsnGlu Val Val Leu 130 135 140 cta gac gcc ccc gtg ggg ctg gtg gcg cgg ttggct gac gag agc ggc 480 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu AlaAsp Glu Ser Gly 145 150 155 160 cac gta gtg ttg cgc tgg ctc ccg ccg cctgag aca ccc atg acg tct 528 His Val Val Leu Arg Trp Leu Pro Pro Pro GluThr Pro Met Thr Ser 165 170 175 cac atc cgc tac gag gtg gac gtc tcg gccggc aac ggc gca ggg agc 576 His Ile Arg Tyr Glu Val Asp Val Ser Ala GlyAsn Gly Ala Gly Ser 180 185 190 gta cag agg gtg gag atc ctg gag ggc cgcacc gag tgt gtg ctg agc 624 Val Gln Arg Val Glu Ile Leu Glu Gly Arg ThrGlu Cys Val Leu Ser 195 200 205 aac ctg cgg ggc cgg acg cgc tac acc ttcgcc gtc cgc gcg cgt atg 672 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe AlaVal Arg Ala Arg Met 210 215 220 gct gag ccg agc ttc ggc ggc ttc tgg agcgcc tgg tcg gag cct gtg 720 Ala Glu Pro Ser Phe Gly Gly Phe Trp Ser AlaTrp Ser Glu Pro Val 225 230 235 240 tcg ctg ctg acg cct agc gac ctg gacccc ctc atc ctg acg ctc tcc 768 Ser Leu Leu Thr Pro Ser Asp Leu Asp ProLeu Ile Leu Thr Leu Ser 245 250 255 ctc atc ctc gtg gtc atc ctg gtg ctgctg acc gtg ctc gcg ctg ctc 816 Leu Ile Leu Val Val Ile Leu Val Leu LeuThr Val Leu Ala Leu Leu 260 265 270 tcc cac cgc cgg gct ctg aag cag aagatc tgg cct ggc atc ccg agc 864 Ser His Arg Arg Ala Leu Lys Gln Lys IleTrp Pro Gly Ile Pro Ser 275 280 285 cca gag agc gag ttt gaa ggc ctc ttcacc acc cac aag ggt aac ttc 912 Pro Glu Ser Glu Phe Glu Gly Leu Phe ThrThr His Lys Gly Asn Phe 290 295 300 cag gtt ggt gct att tct tca gct gtggct gta cca gaa tga 954 Gln Val Gly Ala Ile Ser Ser Ala Val Ala Val ProGlu 305 310 315 7 317 PRT Homo sapiens 7 Met Asp His Leu Gly Ala Ser LeuTrp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 Leu Leu Leu Ala Gly Ala AlaTrp Ala Pro Pro Pro Asn Leu Pro Asp 20 25 30 Pro Lys Phe Glu Ser Lys AlaAla Leu Leu Ala Ala Arg Gly Pro Glu 35 40 45 Glu Leu Leu Cys Phe Thr GluArg Leu Glu Asp Leu Val Cys Phe Trp 50 55 60 Glu Glu Ala Ala Ser Ala GlyVal Gly Pro Gly Asn Tyr Ser Phe Ser 65 70 75 80 Tyr Gln Leu Glu Asp GluPro Trp Lys Leu Cys Arg Leu His Gln Ala 85 90 95 Pro Thr Ala Arg Gly AlaVal Arg Phe Trp Cys Ser Leu Pro Thr Ala 100 105 110 Asp Thr Ser Ser PheVal Pro Leu Glu Leu Arg Val Thr Ala Ala Ser 115 120 125 Gly Ala Pro ArgTyr His Arg Val Ile His Ile Asn Glu Val Val Leu 130 135 140 Leu Asp AlaPro Val Gly Leu Val Ala Arg Leu Ala Asp Glu Ser Gly 145 150 155 160 HisVal Val Leu Arg Trp Leu Pro Pro Pro Glu Thr Pro Met Thr Ser 165 170 175His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Gly Ala Gly Ser 180 185190 Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr Glu Cys Val Leu Ser 195200 205 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe Ala Val Arg Ala Arg Met210 215 220 Ala Glu Pro Ser Phe Gly Gly Phe Trp Ser Ala Trp Ser Glu ProVal 225 230 235 240 Ser Leu Leu Thr Pro Ser Asp Leu Asp Pro Leu Ile LeuThr Leu Ser 245 250 255 Leu Ile Leu Val Val Ile Leu Val Leu Leu Thr ValLeu Ala Leu Leu 260 265 270 Ser His Arg Arg Ala Leu Lys Gln Lys Ile TrpPro Gly Ile Pro Ser 275 280 285 Pro Glu Ser Glu Phe Glu Gly Leu Phe ThrThr His Lys Gly Asn Phe 290 295 300 Gln Val Gly Ala Ile Ser Ser Ala ValAla Val Pro Glu 305 310 315 8 987 DNA Homo sapiens CDS (1)..(984) EpoRIsoform 3, intron 7 unspliced 8 atg gac cac ctc ggg gcg tcc ctc tgg ccccag gtc ggc tcc ctt tgt 48 Met Asp His Leu Gly Ala Ser Leu Trp Pro GlnVal Gly Ser Leu Cys 1 5 10 15 ctc ctg ctc gct ggg gcc gcc tgg gcg cccccg cct aac ctc ccg gac 96 Leu Leu Leu Ala Gly Ala Ala Trp Ala Pro ProPro Asn Leu Pro Asp 20 25 30 ccc aag ttc gag agc aaa gcg gcc ttg ctg gcggcc cgg ggg ccc gaa 144 Pro Lys Phe Glu Ser Lys Ala Ala Leu Leu Ala AlaArg Gly Pro Glu 35 40 45 gag ctt ctg tgc ttc acc gag cgg ttg gag gac ttggtg tgt ttc tgg 192 Glu Leu Leu Cys Phe Thr Glu Arg Leu Glu Asp Leu ValCys Phe Trp 50 55 60 gag gaa gcg gcg agc gct ggg gtg ggc ccg ggc aac tacagc ttc tcc 240 Glu Glu Ala Ala Ser Ala Gly Val Gly Pro Gly Asn Tyr SerPhe Ser 65 70 75 80 tac cag ctc gag gat gag cca tgg aag ctg tgt cgc ctgcac cag gct 288 Tyr Gln Leu Glu Asp Glu Pro Trp Lys Leu Cys Arg Leu HisGln Ala 85 90 95 ccc acg gct cgt ggt gcg gtg cgc ttc tgg tgt tcg ctg cctaca gcc 336 Pro Thr Ala Arg Gly Ala Val Arg Phe Trp Cys Ser Leu Pro ThrAla 100 105 110 gac acg tcg agc ttc gtg ccc cta gag ttg cgc gtc aca gcagcc tcc 384 Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg Val Thr Ala AlaSer 115 120 125 ggc gct ccg cga tat cac cgt gtc atc cac atc aat gaa gtagtg ctc 432 Gly Ala Pro Arg Tyr His Arg Val Ile His Ile Asn Glu Val ValLeu 130 135 140 cta gac gcc ccc gtg ggg ctg gtg gcg cgg ttg gct gac gagagc ggc 480 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu Ala Asp Glu SerGly 145 150 155 160 cac gta gtg ttg cgc tgg ctc ccg ccg cct gag aca cccatg acg tct 528 His Val Val Leu Arg Trp Leu Pro Pro Pro Glu Thr Pro MetThr Ser 165 170 175 cac atc cgc tac gag gtg gac gtc tcg gcc ggc aac ggcgca ggg agc 576 His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Gly AlaGly Ser 180 185 190 gta cag agg gtg gag atc ctg gag ggc cgc acc gag tgtgtg ctg agc 624 Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr Glu Cys ValLeu Ser 195 200 205 aac ctg cgg ggc cgg acg cgc tac acc ttc gcc gtc cgcgcg cgt atg 672 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe Ala Val Arg AlaArg Met 210 215 220 gct gag ccg agc ttc ggc ggc ttc tgg agc gcc tgg tcggag cct gtg 720 Ala Glu Pro Ser Phe Gly Gly Phe Trp Ser Ala Trp Ser GluPro Val 225 230 235 240 tcg ctg ctg acg cct agc gac ctg gac ccc ctc atcctg acg ctc tcc 768 Ser Leu Leu Thr Pro Ser Asp Leu Asp Pro Leu Ile LeuThr Leu Ser 245 250 255 ctc atc ctc gtg gtc atc ctg gtg ctg ctg acc gtgctc gcg ctg ctc 816 Leu Ile Leu Val Val Ile Leu Val Leu Leu Thr Val LeuAla Leu Leu 260 265 270 tcc cac cgc cgg gct ctg aag cag aag atc tgg cctggc atc ccg agc 864 Ser His Arg Arg Ala Leu Lys Gln Lys Ile Trp Pro GlyIle Pro Ser 275 280 285 cca gag agc gag ttt gaa ggc ctc ttc acc acc cacaag ggt aac ttc 912 Pro Glu Ser Glu Phe Glu Gly Leu Phe Thr Thr His LysGly Asn Phe 290 295 300 cag gta ggt ggc ctg gtt gtc ccc tca gtg cct gggctt ccc tgc ttc 960 Gln Val Gly Gly Leu Val Val Pro Ser Val Pro Gly LeuPro Cys Phe 305 310 315 320 ttg cag cca aac tgc agg cct ctc tga 987 LeuGln Pro Asn Cys Arg Pro Leu 325 9 328 PRT Homo sapiens 9 Met Asp His LeuGly Ala Ser Leu Trp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 Leu Leu LeuAla Gly Ala Ala Trp Ala Pro Pro Pro Asn Leu Pro Asp 20 25 30 Pro Lys PheGlu Ser Lys Ala Ala Leu Leu Ala Ala Arg Gly Pro Glu 35 40 45 Glu Leu LeuCys Phe Thr Glu Arg Leu Glu Asp Leu Val Cys Phe Trp 50 55 60 Glu Glu AlaAla Ser Ala Gly Val Gly Pro Gly Asn Tyr Ser Phe Ser 65 70 75 80 Tyr GlnLeu Glu Asp Glu Pro Trp Lys Leu Cys Arg Leu His Gln Ala 85 90 95 Pro ThrAla Arg Gly Ala Val Arg Phe Trp Cys Ser Leu Pro Thr Ala 100 105 110 AspThr Ser Ser Phe Val Pro Leu Glu Leu Arg Val Thr Ala Ala Ser 115 120 125Gly Ala Pro Arg Tyr His Arg Val Ile His Ile Asn Glu Val Val Leu 130 135140 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu Ala Asp Glu Ser Gly 145150 155 160 His Val Val Leu Arg Trp Leu Pro Pro Pro Glu Thr Pro Met ThrSer 165 170 175 His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Gly AlaGly Ser 180 185 190 Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr Glu CysVal Leu Ser 195 200 205 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe Ala ValArg Ala Arg Met 210 215 220 Ala Glu Pro Ser Phe Gly Gly Phe Trp Ser AlaTrp Ser Glu Pro Val 225 230 235 240 Ser Leu Leu Thr Pro Ser Asp Leu AspPro Leu Ile Leu Thr Leu Ser 245 250 255 Leu Ile Leu Val Val Ile Leu ValLeu Leu Thr Val Leu Ala Leu Leu 260 265 270 Ser His Arg Arg Ala Leu LysGln Lys Ile Trp Pro Gly Ile Pro Ser 275 280 285 Pro Glu Ser Glu Phe GluGly Leu Phe Thr Thr His Lys Gly Asn Phe 290 295 300 Gln Val Gly Gly LeuVal Val Pro Ser Val Pro Gly Leu Pro Cys Phe 305 310 315 320 Leu Gln ProAsn Cys Arg Pro Leu 325 10 804 DNA Homo sapiens CDS (1)..(801) EpoRIsoform 4, intron 5 unspliced 10 atg gac cac ctc ggg gcg tcc ctc tgg ccccag gtc ggc tcc ctt tgt 48 Met Asp His Leu Gly Ala Ser Leu Trp Pro GlnVal Gly Ser Leu Cys 1 5 10 15 ctc ctg ctc gct ggg gcc gcc tgg gcg cccccg cct aac ctc ccg gac 96 Leu Leu Leu Ala Gly Ala Ala Trp Ala Pro ProPro Asn Leu Pro Asp 20 25 30 ccc aag ttc gag agc aaa gcg gcc ttg ctg gcggcc cgg ggg ccc gaa 144 Pro Lys Phe Glu Ser Lys Ala Ala Leu Leu Ala AlaArg Gly Pro Glu 35 40 45 gag ctt ctg tgc ttc acc gag cgg ttg gag gac ttggtg tgt ttc tgg 192 Glu Leu Leu Cys Phe Thr Glu Arg Leu Glu Asp Leu ValCys Phe Trp 50 55 60 gag gaa gcg gcg agc gct ggg gtg ggc ccg ggc aac tacagc ttc tcc 240 Glu Glu Ala Ala Ser Ala Gly Val Gly Pro Gly Asn Tyr SerPhe Ser 65 70 75 80 tac cag ctc gag gat gag cca tgg aag ctg tgt cgc ctgcac cag gct 288 Tyr Gln Leu Glu Asp Glu Pro Trp Lys Leu Cys Arg Leu HisGln Ala 85 90 95 ccc acg gct cgt ggt gcg gtg cgc ttc tgg tgt tcg ctg cctaca gcc 336 Pro Thr Ala Arg Gly Ala Val Arg Phe Trp Cys Ser Leu Pro ThrAla 100 105 110 gac acg tcg agc ttc gtg ccc cta gag ttg cgc gtc aca gcagcc tcc 384 Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg Val Thr Ala AlaSer 115 120 125 ggc gct ccg cga tat cac cgt gtc atc cac atc aat gaa gtagtg ctc 432 Gly Ala Pro Arg Tyr His Arg Val Ile His Ile Asn Glu Val ValLeu 130 135 140 cta gac gcc ccc gtg ggg ctg gtg gcg cgg ttg gct gac gagagc ggc 480 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu Ala Asp Glu SerGly 145 150 155 160 cac gta gtg ttg cgc tgg ctc ccg ccg cct gag aca cccatg acg tct 528 His Val Val Leu Arg Trp Leu Pro Pro Pro Glu Thr Pro MetThr Ser 165 170 175 cac atc cgc tac gag gtg gac gtc tcg gcc ggc aac ggcgca ggg agc 576 His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Gly AlaGly Ser 180 185 190 gta cag agg gtg gag atc ctg gag ggc cgc acc gag tgtgtg ctg agc 624 Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr Glu Cys ValLeu Ser 195 200 205 aac ctg cgg ggc cgg acg cgc tac acc ttc gcc gtc cgcgcg cgt atg 672 Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe Ala Val Arg AlaArg Met 210 215 220 gct gag ccg agc ttc ggc ggc ttc tgg agc gcc tgg tcggag cct gtg 720 Ala Glu Pro Ser Phe Gly Gly Phe Trp Ser Ala Trp Ser GluPro Val 225 230 235 240 tcg ctg ctg acg cct agc ggt gag gcc cca ggc gggggt gta gga gga 768 Ser Leu Leu Thr Pro Ser Gly Glu Ala Pro Gly Gly GlyVal Gly Gly 245 250 255 gcc agg gcg aat cac ggg gca agc cca ccg ccc tga804 Ala Arg Ala Asn His Gly Ala Ser Pro Pro Pro 260 265 11 267 PRT Homosapiens 11 Met Asp His Leu Gly Ala Ser Leu Trp Pro Gln Val Gly Ser LeuCys 1 5 10 15 Leu Leu Leu Ala Gly Ala Ala Trp Ala Pro Pro Pro Asn LeuPro Asp 20 25 30 Pro Lys Phe Glu Ser Lys Ala Ala Leu Leu Ala Ala Arg GlyPro Glu 35 40 45 Glu Leu Leu Cys Phe Thr Glu Arg Leu Glu Asp Leu Val CysPhe Trp 50 55 60 Glu Glu Ala Ala Ser Ala Gly Val Gly Pro Gly Asn Tyr SerPhe Ser 65 70 75 80 Tyr Gln Leu Glu Asp Glu Pro Trp Lys Leu Cys Arg LeuHis Gln Ala 85 90 95 Pro Thr Ala Arg Gly Ala Val Arg Phe Trp Cys Ser LeuPro Thr Ala 100 105 110 Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg ValThr Ala Ala Ser 115 120 125 Gly Ala Pro Arg Tyr His Arg Val Ile His IleAsn Glu Val Val Leu 130 135 140 Leu Asp Ala Pro Val Gly Leu Val Ala ArgLeu Ala Asp Glu Ser Gly 145 150 155 160 His Val Val Leu Arg Trp Leu ProPro Pro Glu Thr Pro Met Thr Ser 165 170 175 His Ile Arg Tyr Glu Val AspVal Ser Ala Gly Asn Gly Ala Gly Ser 180 185 190 Val Gln Arg Val Glu IleLeu Glu Gly Arg Thr Glu Cys Val Leu Ser 195 200 205 Asn Leu Arg Gly ArgThr Arg Tyr Thr Phe Ala Val Arg Ala Arg Met 210 215 220 Ala Glu Pro SerPhe Gly Gly Phe Trp Ser Ala Trp Ser Glu Pro Val 225 230 235 240 Ser LeuLeu Thr Pro Ser Gly Glu Ala Pro Gly Gly Gly Val Gly Gly 245 250 255 AlaArg Ala Asn His Gly Ala Ser Pro Pro Pro 260 265 12 747 DNA Homo sapiensCDS (1)..(744) EpoR Isoform 5, exon 6 skipped 12 atg gac cac ctc ggg gcgtcc ctc tgg ccc cag gtc ggc tcc ctt tgt 48 Met Asp His Leu Gly Ala SerLeu Trp Pro Gln Val Gly Ser Leu Cys 1 5 10 15 ctc ctg ctc gct ggg gccgcc tgg gcg ccc ccg cct aac ctc ccg gac 96 Leu Leu Leu Ala Gly Ala AlaTrp Ala Pro Pro Pro Asn Leu Pro Asp 20 25 30 ccc aag ttc gag agc aaa gcggcc ttg ctg gcg gcc cgg ggg ccc gaa 144 Pro Lys Phe Glu Ser Lys Ala AlaLeu Leu Ala Ala Arg Gly Pro Glu 35 40 45 gag ctt ctg tgc ttc acc gag cggttg gag gac ttg gtg tgt ttc tgg 192 Glu Leu Leu Cys Phe Thr Glu Arg LeuGlu Asp Leu Val Cys Phe Trp 50 55 60 gag gaa gcg gcg agc gct ggg gtg ggcccg ggc aac tac agc ttc tcc 240 Glu Glu Ala Ala Ser Ala Gly Val Gly ProGly Asn Tyr Ser Phe Ser 65 70 75 80 tac cag ctc gag gat gag cca tgg aagctg tgt cgc ctg cac cag gct 288 Tyr Gln Leu Glu Asp Glu Pro Trp Lys LeuCys Arg Leu His Gln Ala 85 90 95 ccc acg gct cgt ggt gcg gtg cgc ttc tggtgt tcg ctg cct aca gcc 336 Pro Thr Ala Arg Gly Ala Val Arg Phe Trp CysSer Leu Pro Thr Ala 100 105 110 gac acg tcg agc ttc gtg ccc cta gag ttgcgc gtc aca gca gcc tcc 384 Asp Thr Ser Ser Phe Val Pro Leu Glu Leu ArgVal Thr Ala Ala Ser 115 120 125 ggc gct ccg cga tat cac cgt gtc atc cacatc aat gaa gta gtg ctc 432 Gly Ala Pro Arg Tyr His Arg Val Ile His IleAsn Glu Val Val Leu 130 135 140 cta gac gcc ccc gtg ggg ctg gtg gcg cggttg gct gac gag agc ggc 480 Leu Asp Ala Pro Val Gly Leu Val Ala Arg LeuAla Asp Glu Ser Gly 145 150 155 160 cac gta gtg ttg cgc tgg ctc ccg ccgcct gag aca ccc atg acg tct 528 His Val Val Leu Arg Trp Leu Pro Pro ProGlu Thr Pro Met Thr Ser 165 170 175 cac atc cgc tac gag gtg gac gtc tcggcc ggc aac ggc gca ggg agc 576 His Ile Arg Tyr Glu Val Asp Val Ser AlaGly Asn Gly Ala Gly Ser 180 185 190 gta cag agg gtg gag atc ctg gag ggccgc acc gag tgt gtg ctg agc 624 Val Gln Arg Val Glu Ile Leu Glu Gly ArgThr Glu Cys Val Leu Ser 195 200 205 aac ctg cgg ggc cgg acg cgc tac accttc gcc gtc cgc gcg cgt atg 672 Asn Leu Arg Gly Arg Thr Arg Tyr Thr PheAla Val Arg Ala Arg Met 210 215 220 gct gag ccg agc ttc ggc ggc ttc tggagc gcc tgg tcg gag cct gtg 720 Ala Glu Pro Ser Phe Gly Gly Phe Trp SerAla Trp Ser Glu Pro Val 225 230 235 240 tcg ctg ctg acg cct agc ggg ctctga 747 Ser Leu Leu Thr Pro Ser Gly Leu 245 13 248 PRT Homo sapiens 13Met Asp His Leu Gly Ala Ser Leu Trp Pro Gln Val Gly Ser Leu Cys 1 5 1015 Leu Leu Leu Ala Gly Ala Ala Trp Ala Pro Pro Pro Asn Leu Pro Asp 20 2530 Pro Lys Phe Glu Ser Lys Ala Ala Leu Leu Ala Ala Arg Gly Pro Glu 35 4045 Glu Leu Leu Cys Phe Thr Glu Arg Leu Glu Asp Leu Val Cys Phe Trp 50 5560 Glu Glu Ala Ala Ser Ala Gly Val Gly Pro Gly Asn Tyr Ser Phe Ser 65 7075 80 Tyr Gln Leu Glu Asp Glu Pro Trp Lys Leu Cys Arg Leu His Gln Ala 8590 95 Pro Thr Ala Arg Gly Ala Val Arg Phe Trp Cys Ser Leu Pro Thr Ala100 105 110 Asp Thr Ser Ser Phe Val Pro Leu Glu Leu Arg Val Thr Ala AlaSer 115 120 125 Gly Ala Pro Arg Tyr His Arg Val Ile His Ile Asn Glu ValVal Leu 130 135 140 Leu Asp Ala Pro Val Gly Leu Val Ala Arg Leu Ala AspGlu Ser Gly 145 150 155 160 His Val Val Leu Arg Trp Leu Pro Pro Pro GluThr Pro Met Thr Ser 165 170 175 His Ile Arg Tyr Glu Val Asp Val Ser AlaGly Asn Gly Ala Gly Ser 180 185 190 Val Gln Arg Val Glu Ile Leu Glu GlyArg Thr Glu Cys Val Leu Ser 195 200 205 Asn Leu Arg Gly Arg Thr Arg TyrThr Phe Ala Val Arg Ala Arg Met 210 215 220 Ala Glu Pro Ser Phe Gly GlyPhe Trp Ser Ala Trp Ser Glu Pro Val 225 230 235 240 Ser Leu Leu Thr ProSer Gly Leu 245 14 22 DNA Artificial sequence Synthetic oligonucleotide14 tcaagcggct gcttccttcc aa 22 15 24 DNA Artificial sequence Syntheticoligonucleotide 15 gcagggagcg tacagagggt ggag 24 16 24 DNA Artificialsequence Synthetic oligonucleotide 16 gaagaaatag caccaacctg gaag 24 1722 DNA Artificial sequence Synthetic oligonucleotide 17 ctgacgcctagcgacctgga cc 22 18 21 DNA Artificial sequence Synthetic oligonucleotide18 gcagtttggc tgcaagaagc a 21 19 20 DNA Artificial sequence Syntheticoligonucleotide 19 ggagccaggg cgaatcacgg 20 20 20 DNA Artificialsequence Synthetic oligonucleotide 20 gccttcaaac tcgctctctg 20 21 21 DNAArtificial sequence Synthetic oligonucleotide 21 gcttcagagc ccgctaggcg t21

That which is claimed is:
 1. An isolated nucleic acid selected from thegroup consisting of a nucleic acid encoding erythropoietin receptorisoform 1 and having the sequence given herein as SEQ ID NO: 4; anucleic acid encoding erythropoietin receptor isoform 2 and having thesequence given herein as SEQ ID NO: 6; a nucleic acid encodingerythropoietin receptor isoform 3 and having the sequence given hereinas SEQ ID NO: 8; a nucleic acid encoding erythropoietin receptor isoform4 and having the sequence given herein as SEQ ID NO: 10; a nucleic acidencoding erythropoietin receptor isoform 5 and having the sequence givenherein as SEQ ID NO: 12; a nucleic acid that encodes the opposite strandof a nucleic acid as set forth above.
 2. The nucleic acid according toclaim 1 encoding erythropoietin receptor isoform 1 and having thesequence given herein as SEQ ID NO:
 4. 3. The nucleic acid according toclaim 1 encoding erythropoietin receptor isoform 2 and having thesequence given herein as SEQ ID NO:
 6. 4. The nucleic acid according toclaim 1 encoding erythropoietin receptor isoform 3 and having thesequence given herein as SEQ ID NO:
 8. 5. The nucleic acid according toclaim 1 encoding erythropoietin receptor isoform 4 and having thesequence given herein as SEQ ID NO:
 10. 6. The nucleic acid according toclaim 1 encoding erythropoietin receptor isoform 5 and having thesequence given herein as SEQ ID NO:
 12. 7. The nucleic acid according toclaim 1, wherein said nucleic acid is an RNA.
 8. A recombinant nucleicacid comprising a promoter operatively associated with a nucleic acidaccording to claim
 1. 9. A host cell containing a recombinant nucleicacid according to claim 8 and which expresses the encoded erythropoetinreceptor isoform.
 10. An isolated protein encoded by a nucleic acidaccording to claim
 1. 11. An antibody that selectively binds to aprotein according to claim
 10. 12. The antibody according to claim 11coupled to a detectable group.
 13. The antibody according to claim 11coupled to a solid support.
 14. The antibody according to claim 11,wherein said antibody is a monoclonal antibody.
 15. The antibodyaccording to claim 11, wherein said antibody is a polyclonal antibody.16. An oligonucleotide probe that specifically binds to a nucleic acidaccording to claim
 1. 17. A method of screening a subject for cancer,comprising: detecting the presence or absence of nucleic acid accordingto claim 1 in said subject, the presence of such a nucleic acidindicating said subject is afflicted with or at risk of developingcancer.
 18. The method according to claim 17, wherein said cancer isbreast, cervix, colon, lung, ovarian or prostate cancer.
 19. The methodaccording to claim 17, wherein said detecting step is carried out bycollecting a biological sample from said subject, and then detecting thepresence or absence of said nucleic acid in said biological sample. 20.A method of screening a subject for cancer, comprising: detecting thepresence or absence of a protein encoded by a nucleic acid according toclaim 1 in said subject, the presence of such a protein indicating saidsubject is afflicted with or at risk of developing cancer.
 21. Themethod according to claim 20, wherein said cancer is breast, cervix,colon, lung, ovarian or prostate cancer.
 22. The method according toclaim 20, wherein said detecting step is carried out by collecting abiological sample from said subject, and then detecting the presence orabsence of said protein in said biological sample.
 23. The methodaccording to claim 20, wherein said detecting step is carried out byimmunoassay.
 24. The method according to claim 20, wherein saiddetecting step is carried out by detecting nucleic acid that encodessaid protein.